The annual meeting of the European Association for the Study of Diabetes (EASD) took place this year in Berlin, Germany. The present text offers a selection of topics relevant for the field of type 2 diabetes mellitus (T2DM) discussed during that meeting.
Long-acting GLP-1 receptor agonists (GLP-1RAs) have extensively shown their utility in the treatment of T2DM by reducing HbA1c levels, body weight and offering cardiovascular protection in high risk populations. The currently approved medications belonging to this drug class have been developed for subcutaneous administration, requiring daily or weekly injections. Semaglutide, a GLP-1RA approved for subcutaneous weekly administration, is now being developed for oral administration together with an absorption enhancer called SNAC. The PIONEER program is a phase 3 program designed to assess efficacy and safety of oral semaglutide. PIONEER-1 is the first study of this program, which was performed in 703 patients with T2DM. The primary efficacy parameter was HbA1c, which was evaluated at baseline and after 26 weeks of treatment with 3, 7 and 14 mg of oral semaglutide taken daily. The estimated treatment differences in HbA1c reduction compared to placebo were:
- 3 mg: -0.7% (-0.9; -0.5, 95%CI, p<0.001)
- 7 mg: -1.2% (-1.5; -1.0, 95%CI, p<0.001)
- 14 mg -1.4% (-1.7; -1.2, 95%CI, p<0.001)
The estimated treatment differences in body weight reduction compared to placebo were:
- 3 mg: -0.2 kg (-1.0; 0.6, 95%CI), not significant.
- 7 mg -1.0 kg (-1.8; -0.2, 95%CI, p<0.05)
- 14 mg -2.6 kg (-3.4; -1.8, 95%CI, p<0.001)
Overall, the adverse events and the safety profile of oral semaglutide were consistent with that of other GLP-1RAs.
The upcoming studies of the PIONEER program include the evaluation of oral semaglutide against active comparators and in special populations. Moreover, in line with the results of the SUSTAIN-6 trial , the benefits of oral semaglutide in cardiovascular (CV) outcomes in a population at risk should be studied. The other important question to be answered is the utility of semaglutide as drug for of weight management, given its structural similarity but superior body weight loss compared to liraglutide, currently approved by the U.S. Food and Drug Administration (FDA) for weight reduction.
Studying diabetic kidney disease
Diabetic kidney disease affects approximately 40% of patients with T2DM. Some trials with GLP-1RAs and sodium-glucose cotransporter-2 (SGLT2) inhibitors studied the effects of these drugs in the progression of chronic kidney disease (CKD) and whether the presence of kidney function modulates the occurrence of CV events. The following trials reported results relevant for patients with CKD:
EXSCEL: this trial included 14,752 patients with T2DM, which were randomised to receive either placebo or exenatide 2 mg once weekly. The primary outcome was a composite of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The results showed that the reduction in incidence of major adverse cardiovascular events did just miss statistical significance between patients who received exenatide and those who received placebo . In univariate subgroup analyses, there was no significant interaction between randomised treatment and renal function, either based on estimated glomerular filtration rate (eGFR) thresholds (± 60 mL/min/1.73m2; p for interaction = 0.12) or on CKD stages (p for interaction = 0.51). That means that risk profile did not change in population with altered kidney function.
- LEADER: this trial was performed in over 9,000 patients with T2DM. Patients received either liraglutide 1.8 once daily or placebo and the cardiovascular outcomes were evaluated . The median follow-up was 3.8 years. The study showed a 13% reduction in occurrence of cardiovascular endpoints in the liraglutide group compared to placebo (p = 0.01 for superiority). A post-hoc subgroup analysis showed that after stratification for eGFR, subjects with values >60 mL/min/1.73m2 had a greater reduction (31%) in the occurrence of the primary endpoint (hazard ratio 0.69; 0.57 - 0.85; 95% CI, p=0.01) According to these results patients with CKD had a greater benefit of taking liraglutide in terms of reduction in CV events and mortality.
- CANVAS: this trial included 10,142 patients with T2DM and evaluated the efficacy of canagliflozin 100 and 300 mg q.d. compared to placebo . The primary endpoint included CV death, non-fatal myocardial infarction and non-fatal stroke. Subjects on canagliflozin had 14% less CV events (hazard ratio 0.86; 95% CI, 0.75 – 0.97). The primary outcome and other CV outcomes were assessed in participants by baseline eGFR (<45, 45-<60, 60-<90, and ≥90 ml/min/1.73 m2). The relative effects on the primary and other CV outcomes were comparable across four eGFR levels, with possible heterogeneity for the outcome of stroke, suggesting that the cardioprotective benefits of canagliflozin are similar across different levels of kidney function.
- SUSTAIN-6: in this study 3,927 subjects with T2DM were randomised to receive semaglutide s.c. 0.5 mg, 1 mg or placebo . The primary endpoint included CV death, non-fatal myocardial infarction and non-fatal stroke. Subjects on semaglutide had a significant reduction of 26% in the primary outcome (hazard ratio, 0.74; 95% CI, 0.58 - 0.95). Changes in kidney function were evaluated in subjects categorised by baseline eGFR (mL/min/1.73 m2: normal [≥90], mild impairment [<90], moderate impairment [<60] and severe impairment [<30]). The percentage of subjects suffering new or worsening nephropathy were:
4.4% with low dose semaglutide and 6.6% with low dose placebo.
2.8% with high dose semaglutide and 5.5% with high dose placebo.
These studies demonstrate that the results of trials investigating CV outcomes with GLP1-RA are not dependent on the renal function. Moreover, they appear to suggest that this collective of patients could experience a renal benefit of taking these medications. With respect to SGLT2 inhibitors, they seem to have a kidney-protective effect that needs to be further studied.
- SAR425899: the company Sanofi presented this novel dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist. The study evaluated two doses of the substance (180 and 90 μg) after 28 weeks. The compound showed a reduction from baseline in fasting plasma glucose of 42 mg/dL with the low dose and of 54.8 mg/dL with the high dose. Subjects on high doses had a mean weight reduction of 5.5 kg (significantly higher compared to placebo at p<0.001) from baseline and of 2.9 kg with the low dose.
- LY3298176: this novel molecule from the company Eli Lilly, has activity on GLP-1 and gastric inhibitory polypeptide (GIP) receptors. Four doses of LY3298176, dulaglutide as active comparator and placebo were investigated in 26-week study. The doses of LY3298176 were 1, 5, 10 and 15 mg administered once weekly. Mean changes from baseline in HbA1c with LY3298176 were -1.06% for 1 mg, -1.73% for 5 mg, -1.89% for 10 mg, and -1.94% for 15 mg, compared with -0.06% for placebo. Changes in mean bodyweight ranged from -0.9 kg to -11 kg for LY3298176 (vs -0.4 kg for placebo, -2.7 kg for dulaglutide) with an acceptable safety and tolerability profile  . These results appear to be very promising, particularly with regard to weight management. The question that remains unanswered is which mechanisms are involved in the development for such impressive results.
Linagliptin is dipeptidyl peptidase-4 (DPP4) inhibitor developed by Boehringer Ingelheim for treatment of T2DM. In this study 6,991 subjects with T2DM were randomised to receive linagliptin 5 mg daily or placebo. The median treatment exposure was 1.9 years. The primary endpoint consisted of the composite major adverse cardiac events (MACE) outcome including CV death, non-fatal myocardial infarction or non-fatal stroke. The trial met its primary endpoint, which was non-inferiority in the 3-point MACE outcome (hazard ratio 1.02, 95% CI, 0.89 - 1.17) However, linagliptin was not superior to placebo in the CV outcomes, which was also a pre-specified primary endpoint. All-cause mortality was also not different in patients taking linagliptine compared to placebo (hazard ratio 0.98, 95% CI, 0.84 - 1.13). These results confirm the CV safety of this particular DDP4 inhibitor.